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Efficacy and Tolerability of Add-on Cannabidiol in Pediatric Patients with Drug-Resistant Epilepsy: An Open Exploratory Interventional Study in México "Efficacy and Tolerability of Add-on Cannabidiol in Pediatric Patients with Drug-Resistant

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Keywords: Resistant Epilepsy; Seizures; Pediatric Epilepsy; Cannabidiol Purpose: To describe the experience of a private neuropediatric clinic on using standardized cannabidiol (CBD) product (RSHO-X™. Medical Marijuana Inc. San Diego, CA, USA), to treat pediatric patients diagnosed with drug-resistant epilepsy (RE) in México. Methods: Forty-six (46) pediatric patients (age: 1-17 years) with severe, drug-resistant epilepsy, who were receiving stable doses of antiepileptic drugs (AED) before study entry. 37 patients were evaluable based on protocol compliance (adherence to treatment and completed control follow-ups at 3, 6, 9 and 12 months). The selected formula contained 5000 mg CBD in 236 mL MCT coconut oil and was free of THC. The initial CBD doses treatment was (1-2 mg/kg/day) and progressively titrate the dose up to 5 mg/kg/day during the first 4 weeks to reduce the seizure frequency by 50% or more. The primary efficacy endpoint was the median percentage change in the mean monthly seizure frequency at the end of the study period. The tolerability was evaluated base on the record of the side effects. Results: The treatment yielded a positive effect on seizure reduction after 3 months. Most of the children 25/37 (67.5%) reported a reduction in seizure frequency; a 100% reduction in 1 (2.2%), more than 80% reduction in 11 (25%), 50% or more in 25 (67.5%) and less than 50% reduction was reported in 12 (27.2%) patients, respectively. Two patients reported an increase in seizures (4.3%), two no improvement (4.3%) and three (6.5%) abandoned with adverse effects dropped out of follow-up before 3 months are not included in this analysis. Adverse reactions occurred in 11/37 (29.7%) patients, with a mild grade in 10 subjects and moderate in 1 subject respectively. Conclusion: The results of this study on the treatment of CBD (RSHO-X™) oil for drug-resistant epilepsy in children and adolescents are promising with good efficacy and tolerability. Abbreviations
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1Pediatric Neurology, Tecnológico de Monterrey, México
2JKMD Global Medical Solutions, Costa Mesa, CA, USA
3MJNA Group LLC., San Diego, CA, USA
Citation: Carlos G Aguirre Velázquez., et al     
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Keywords: Resistant Epilepsy; Seizures; Pediatric Epilepsy; Cannabidiol
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 

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   

Citation: Carlos G Aguirre Velázquez., et al   
EC Neurology 

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



     
    
      
 in vivoin vitro 










    
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
pre      




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 
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

Citation: Carlos G Aguirre Velázquez., et al   
EC Neurology 
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of seizures.
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

Citation: Carlos G Aguirre Velázquez., et al   
EC Neurology 
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 
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
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   

        
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  

 

Figure 1: Flow chart of consecutive pediatric cases of drug-resistant epilepsy treated with Cannabidiol (CBD).
Citation: Carlos G Aguirre Velázquez., et al   
EC Neurology 



s
 
 
 
 

• 
• 
• 

2
1
1

• 
• 

1

• 
• 
• 
• 
• 

1
1
1
1

• 
• 
• 
• 
• 
• 
• 

2
2
1
1
1
1
1

• 
• 
• 




 
 
















Table 1: Key baseline characteristics in 37 cases of the trial group.
Citation: Carlos G Aguirre Velázquez., et al   
EC Neurology 



  
 37 100
 22 
  
  
 10 
  
  
  
  
 2
 1
 1
 1
Table 2: Seizures type.
   

In regression linear graph it is observable the grouping of the less monthly frequency of seizures in 2 to 4 mg/kg/day CBD
doses.
Figure 2: Relationship of CBD dose and crisis reduction in 37 cases.
Citation: Carlos G Aguirre Velázquez., et al   
EC Neurology 




  


   

 012
 0 0  
 0 1 0 0
 0 0 0 0
 0 0 0 0
 110
    
Table 3: Percentage change average in monthly seizure frequency of different epilepsy etiology in 37 cases.
     





Figure 3: Monthly frequency of seizures in patients before and after Cannabidiol (RSHO-X™) treatment.
Citation: Carlos G Aguirre Velázquez., et al   
EC Neurology 



   
  
  
  

Table 4: Compared CBD only vs CBD and Clobazam in % of reduction of seizures.
CBD: Cannabidiol, CLB: Clobazam.



 
 
 
 
 
 
 
 
 
 
Table 5: Side Effects Reported after the Introduction of CBD (RSHO-X™).



   
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 


et al.

 

 


Citation: Carlos G Aguirre Velázquez., et al   
EC Neurology 
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      

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   
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
  
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     
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
1. et al
Epilepsia
2. New England Journal of Medicine 
 European Journal of Neurol-
ogy 
   et al           
Epilepsia
Citation: Carlos G Aguirre Velázquez., et al   
EC Neurology 
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

 et alThe Lancet Neurol-
ogy
 et alJournal of Clinical Pharmacy and Therapeutics.
   Annual Review of Neuroscience 

 New England Journal of Medicine 
 et alEpilepsy Currents 
10. et alNeurology

11. et al
Epilepsy and Behavior
12. et alEpilepsy and Be-
havior
 
 Plasticidad y Restau Neurol

 Journal of Epilepsy Research
 et al
Epilepsia 
 et alSeizure

 Zgair A., et al            
American Journal of Translational Research 
    
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20. et alEpilepsy and Behavior
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21. Epilepsy and Behavior
22. et alEpilepsy and Behavior

  et al  
Journal of Neurology, Neurosurgery and Psychiatry
Citation: Carlos G Aguirre Velázquez., et al   
EC Neurology 
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., et al.

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 et al   Neurology 
e1211.
 et al
Lancet
 et al
Frontiers in Neurology 
 Frontiers in Plant
Science 
... Evidences of use of cannabis in epilepsy[53,[55][56][57][59][60][61][62][63][64][65][66][67][68] ...
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i>Cannabis sativa L. is an annual herbaceous dioecious plant which was first cultivated by agricultural human societies in Asia. Over the period of time, various parts of the plant like leaf, flower, and seed were used for recreational as well as therapeutic purposes. The main chemical components of Cannabis sativa are termed as cannabinoids, among them the key psychoactive constituent is Δ-9-tetrahydrocannabinol and cannabidiol (CBD) as active nonpsychotic constituent. Upon doing extensive literature review, it was found that cannabis has been widely studied for a number of disorders. Very recently, a pure CBD formulation, named Epidiolex, got a green flag from both United States Food and Drug Administration and Drug Enforcement Administration for 2 rare types of epilepsies. This laid a milestone in medical cannabis research. This review intends to give a basic and extensive assessment, from past till present, of the ethnological, plant, chemical, pharmacological, and legal aspects of C. sativa . Further, this review contemplates the evidence the studies obtained of cannabis components on Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis, multiple sclerosis, emesis, epilepsy, chronic pain, and cancer as a cytotoxic agent as well as a palliative therapy. The assessment in this study was done by reviewing in extensive details from studies on historical importance, ethnopharmacological aspects, and legal grounds of C. sativa from extensive literature available on the scientific databases, with a vision for elevating further pharmaceutical research to investigate its total potential as a therapeutic agent.
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The topic of Cannabis curries controversy in every sphere of influence, whether politics, pharmacology, applied therapeutics or even botanical taxonomy. Debate as to the speciation of Cannabis, or a lack thereof, has swirled for more than 250 years. Because all Cannabis types are eminently capable of cross-breeding to produce fertile progeny, it is unlikely that any clear winner will emerge between the “lumpers” vs. “splitters” in this taxonomical debate. This is compounded by the profusion of Cannabis varieties available through the black market and even the developing legal market. While labeled “strains” in common parlance, this term is acceptable with respect to bacteria and viruses, but not among Plantae. Given that such factors as plant height and leaflet width do not distinguish one Cannabis plant from another and similar difficulties in defining terms in Cannabis, the only reasonable solution is to characterize them by their biochemical/pharmacological characteristics. Thus, it is best to refer to Cannabis types as chemical varieties, or “chemovars.” The current wave of excitement in Cannabis commerce has translated into a flurry of research on alternative sources, particularly yeasts, and complex systems for laboratory production have emerged, but these presuppose that single compounds are a desirable goal. Rather, the case for Cannabis synergy via the “entourage effect” is currently sufficiently strong as to suggest that one molecule is unlikely to match the therapeutic and even industrial potential of Cannabis itself as a phytochemical factory. The astounding plasticity of the Cannabis genome additionally obviates the need for genetic modification techniques.
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This meta-analysis paper describes the analysis of observational clinical studies on the treatment of refractory epilepsy with cannabidiol (CBD)-based products. Beyond attempting to establish the safety and efficacy of such products, we also investigated if there is enough evidence to assume any difference in efficacy between CBD-rich extracts compared to purified CBD products. The systematic search took place in February/2017 and updated in December/2017 using the keywords “epilepsy” or “Dravet” or “Lennox-Gastaut” or “CDKL5” combined with “Cannabis,” “cannabinoid,” “cannabidiol,” or “CBD” resulting in 199 papers. The qualitative assessment resulted in 11 valid references, with an average impact factor of 8.1 (ranging from 1.4 to 47.8). The categorical data of a total of 670 patients were analyzed by Fischer test. The average daily dose ranged between 1 and 50 mg/kg, with treatment length from 3 to 12 months (mean 6.2 months). Two thirds of patients reported improvement in the frequency of seizures (399/622, 64%). There were more reports of improvement from patients treated with CBD-rich extracts (318/447, 71%) than patients treated with purified CBD (81/223, 36%), with statistical significance (p < 0.0001). Nevertheless, when the standard clinical threshold of a “50% reduction or more in the frequency of seizures” was applied, only 39% of the individuals were considered “responders,” and there was no difference (p = 0.56) between treatments with CBD-rich extracts (97/255, 38%) and purified CBD (94/223, 42%). Patients treated with CBD-rich extracts reported lower average dose (6.1 mg/kg/day) than those using purified CBD (27.1 mg/kg/day). The reports of mild (109/285 vs. 291/346, p < 0.0001) and severe (23/285 vs. 77/346, p < 0.0001) adverse effects were more frequent in products containing purified CBD than in CBD-rich extracts. CBD-rich extracts seem to present a better therapeutic profile than purified CBD, at least in this population of patients with refractory epilepsy. The roots of this difference is likely due to synergistic effects of CBD with other phytocompounds (aka Entourage effect), but this remains to be confirmed in controlled clinical studies.
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Objective: To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome. Methods: Patients aged 4-10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metaboliteN-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, ECGs, adverse events (AEs), seizure frequency, and suicidality. Results: Thirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups, and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose-proportional (AUC0-t). CBD did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed. Conclusions: Exposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. CBD resulted in more AEs than placebo but was generally well-tolerated. Classification of evidence: This study provides Class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well-tolerated.
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Review evidence for cannabinoids as adjunctive treatments for treatment-resistant epilepsy. Systematic search of Medline, Embase and PsycINFO was conducted in October 2017. Outcomes were: 50%+ seizure reduction, complete seizure freedom; improved quality of life (QoL). Tolerability/safety were assessed by study withdrawals, adverse events (AEs) and serious adverse events (SAEs). Analyses were conducted in Stata V.15.0. 36 studies were identified: 6 randomised controlled trials (RCTs), 30 observational studies. Mean age of participants was 16.1 years (range 0.5–55 years). Cannabidiol (CBD) 20 mg/kg/day was more effective than placebo at reducing seizure frequency by 50%+(relative risk (RR) 1.74, 95% CI 1.24 to 2.43, 2 RCTs, 291 patients, low Grades of Recommendation, Assessment, Development and Evaluation (GRADE) rating). The number needed to treat for one person using CBD to experience 50%+ seizure reduction was 8 (95% CI 6 to 17). CBD was more effective than placebo at achieving complete seizure freedom (RR 6.17, 95% CI 1.50 to 25.32, 3 RCTs, 306 patients, low GRADE rating), and improving QoL (RR 1.73, 95% CI 1.33 to 2.26), however increased risk of AEs (RR 1.24, 95% CI 1.13 to 1.36) and SAEs (RR 2.55, 95% CI 1.48 to 4.38). Pooled across 17 observational studies, 48.5% (95% CI 39.0% to 58.1%) of patients reported 50%+ reductions in seizures; in 14 observational studies 8.5% (95% CI 3.8% to 14.5%) were seizure-free. Twelve observational studies reported improved QoL (55.8%, 95% CI 40.5 to 70.6); 50.6% (95% CI 31.7 to 69.4) AEs and 2.2% (95% CI 0 to 7.9) SAEs. Pharmaceutical-grade CBD as adjuvant treatment in paediatric-onset drug-resistant epilepsy may reduce seizure frequency. Existing RCT evidence is mostly in paediatric samples with rare and severe epilepsy syndromes; RCTs examining other syndromes and cannabinoids are needed. PROSPERO registration number CRD42017055412.
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Background: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients. Methods: In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690. Findings: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment. Interpretation: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial. Funding: GW Pharmaceuticals.